Cocaine dependence is a major public health concern in the United States with no currently FDA approved treatments. Recent animal research has demonstrated that chronic cocaine use alters brain circuitry involved with motivation and reward, and has identified several novel targets for therapeutic intervention. However, most of the findings from this research have not been evaluated in humans. Functional neuroimaging techniques provide unique opportunities to examine the generalizability of animal research findings to humans. However, whereas most functional neuroimaging studies have focused on comparisons between cocaine dependent and cocaine-naive individuals, recent animal models of addiction have emphasized the importance of examining differences between voluntary (or "recreational") and compulsive (or "dependent") cocaine users in terms of their neural responses to cocaine cues. The latter comparison is critically important because, unlike for cocaine-naive individuals, cocaine stimuli are motivationally salient for recreational users and are expected to activate centers of the brain involved in reward. In sum, identifying differences in brain activation to cocaine cues between dependent and recreational cocaine users could potentially provide important insight into the transition from voluntary to compulsive cocaine use in humans. In Aim 1 of the proposed study, 30 dependent and 30 recreational cocaine users will participate in a functional Magnetic Resonance Imaging (fMRI) experiment including a cocaine cue exposure task, where they will be asked to view neutral and cocaine- related pictures. In accordance with findings from animal research, we hypothesize that dependent cocaine users will have significantly greater dorsal striatal and significantly less ventral striatal and frontal activity, when exposed to cocaine cues, as compared to recreational users. Recent rodent research has also established that rats characterized by greater impulsivity prior to cocaine exposure are far more likely to develop compulsive patterns of cocaine use relative to non-impulsive rats. Human neuroimaging research has demonstrated that cocaine-dependent individuals experience less activation of frontal brain regions involved in behavioral constraint (e.g., anterior cingulate) when asked to inhibit a prepotent response as compared to cocaine-naive individuals. However, no studies have compared dependent and recreational cocaine users in terms of their frontal brain activation associated with response inhibition. Thus, to investigate Aim 2 of the proposed study, the above dependent and recreational cocaine users will complete a response inhibition (i.e., go no-go) fMRI task. We hypothesize that dependent cocaine users will demonstrate significantly less anterior cingulate and other frontal brain activity, when asked to inhibit a prepotent response, as compared to recreational cocaine users. Findings from the proposed study will help to extend recent animal research regarding changes in neurocircuitry associated with cocaine addiction to humans, and in doing so, will provide support for the development of novel therapeutic agents. Importantly, the proposed study is consistent with NIDA's mission, "to bring the power of science to bear on drug abuse and addiction," and especially with NIDA's prevention objective, "to improve and expand our understanding of basic neurobiology as it relates to the brain circuitry underlying drug abuse and addiction." PUBLIC HEALTH RELEVANCE: Recent animal research has demonstrated that cocaine addiction is associated with a number of pathological changes in the brain's motivational and reward circuitry. Although these findings may offer great promise in identifying novel targets for therapeutic interventions for cocaine addiction, more research is needed to determine how well these animal research findings apply to humans. To this end, the proposed study will examine differences in brain activation to cocaine cues and response inhibition (a facet of impulsivity that is found to predict the development of cocaine addiction) between recreational (or "voluntary") and dependent (or "compulsive") cocaine users using functional Magnetic Resonance Imaging.